It is known that Parkinson's disease, namely parkinsonism is such disease which is caused by abnormal reduction or decrease in the levels of catecholamines such as dopamine, noradrenaline and adrenaline present in the brain of the human beings (see, for example, "Advances in Neurology" Vol. 24, pages 29-36 (1979) and Vol. 40, pages 467-473 (1984); and the "Biochemical Medicine" Vol. 27, pages 317-324 (1982)). It is expectable that the parkinsonism can be treated therapeutically by supplementing externally the biogenic catecholamines or their precursors into the parkinsonian patients so that the levels of the catecholamines as descreased can be increased and restored to the normal levels in the brain. L-3,4-dihydroxyphenylalanine (L-DOPA) and L-threo-3-(3,4-dihydroxyphenyl)serine (L-threo-DOPS) as synthetized are administered to parkinsonian patients as such a precursor of said catecholamine which would be capable of penetrating and transferring into the parkinsonian brain through the blood-brain barrier and increasing the abnormally decreased levels of the brain catecholamines to the normal levels, even when such precursor is administered intraperitoneally or intravenously.
It was fairly long ago that 3-(3,4-dihydroxyphenyl)serine (abbreviated as DOPS) was first synthetized, but only in recent years, physiological and pharmacological activities of this known compound (DOPS) have become noticeably interesting in the related field of the art. Thus, several years ago, it was reported that L-threo-DOPS is useful as an antiparkinsonian drug for use in therapeutic treatment of Parkinson's disease (see Japanese patent application prepublication "Kokai" No. 125630/77 and U.S. Pat. No. 4,319,040), and also as an antidepressive agent for use in therapeutic treatment of mental disease, depression (see Japanese patent application prepublication "Kokai" No. 20747/80 and U.S. Pat. No. 3,920,728), and further that L-erythro-DOPS is useful as a hypertensive agent for use in therapeutic treatment of hypertension. Judging from these useful biological activities of DOPS, we, the present inventors have an expection that new N-methylated derivatives of DOPS will show any biological activities similar to or higher than or more valuable than those of DOPS and thus be useful as medical substance in the therapeutic applications.
Furthermore, it is known that the four stereoisomers of DOPS includes L-erythro-DOPS, D-erythro-DOPS, L-threo-DOPS and D-threo-DOPS. Biochemical and histochemical investigations of these four stereoisomers of DOPS have revealed that L-erythro-DOPS and L-threo-DOPS as intraperitoneally administered in rats are readily decarboxylated in vivo, leading to an accumulation of noradrenaline (namely, norepinephrine) in heart, and that the accumulation of noradrenaline of the unnatural (d)-form in brain is significant after the intraperitoneal administration of L-erythro-DOPS, whereas the accumulation of noradrenaline of the natural (l)-form in brain is negligible after the intraperitoneal administration of L-threo-DOPS but the accumulation of the natural (l)-noradrenaline in the brain becomes marked after direct injection of L-threo-DOPS into a cerebral ventricle, indicating that L-threo-DOPS as given intraperitoneally can hardly penetrate and transfer through the blood-brain barrier into the brain and is considered to be substantially not effective to increase the level of noradrenaline in the brain (see "The Journal of Pharmacology and Experimental Therapeutics" Vol. 193. No. 2, pages 523-530 (1975)). It also has been revealed in said literat that intraperitoneal administration of high dosages of D-erythro-DOPS or D-threo-DOPS causes a slight increase in the levels of noradrenaline in heart and brain, indicating that D-erythro-DOPS and D-threo-DOPS are probably not decarboxylated in vivo to a major extent.
We have now succeeded in synthetizing firstly as the new compound threo-3-(3,4-dihydroxyphenyl)-N-methylserine, either in the DL-form or in the L-form (as viewed from the .alpha.-carbon atom of the serine moiety) with starting from DL-threo-DOPS, and we have now found that, in contrast to the known L-threo-DOPS, the new compound, L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine, even when administered intraperitoneally or intravenously in mice, can surprisingly penetrate and transfer through the blood-brain barrier into the brain so that a quantity of L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine is detectable in the brain of the treated mice, with an increased level of adrenaline in the brain which is significantly higher than the normal level of adrenaline in the brain of the mice untreated, and further we have now found that L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine can hardly be decarboxylated into adrenaline in "in vitro" tests where L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine is treated with such a homogenates of the whole brains of mice which is containing therein some catecholamine-related enzymes, including at least an enzyme for converting L-threo-DOPS into noradrenaline as well as an enzyme, phenylethanolamine N-methyltransferase (PNMT) for converting noradrenaline as substrate into adrenaline, in contrast to the experimental fact that L-threo-DOPS can be decarboxylated into noradrenaline in the "in vitro" tests where L-threo-DOPS is treated with the above-mentioned homogenate of the whole brains of mice.
We have not yet been able to elucidate why the level of adrenaline in brain can virtually be increased by intraperitoneal or intravenous injection of the new compound L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine which can hardly be decarboxylated in the "in vitro" tests using the homogenate of the whole brains containing all the enzymes of the brain.
From these experimental facts as above, we have expected that the new compound, L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine which may also be termed as L-threo-adrenalinecarboxylic acid, and a pharmaceutically acceptable salt and hydrate thereof will be more advantageous and more promising as medicinal agent than anyone of the known four stereoisomers of DOPS.
It is further known that the L-threo isomer of DOPS exhibits the antiparkinsonian activity while the L-erythro isomer thereof cannot exhibit such medicinal activity (see Japanese patent application prepublication "Kokai" No. 125630/77 as referred to herein before). Besides, T. Nagatsu, one of the inventors, has found the fact that not only noradrenaline, but also adrenaline in the brain are decreased in patients with Parkinson's disease. From this point of view, we presume that the L-threo form will be necessary for the antiparkinsonian activity of the 3-(3,4-dihydroxyphenyl)-N-methylserine we have now synthetized. And we have now confirmed that the DL-form and the L-threo isomer of 3-(3,4-dihydroxyphenyl)-N-methylserine synthetized by us are virtually highly effective for the medicinal applications.
For our acknowledgement, we may add that a previous approach to the synthesis of 3-(3,4-dihydroxyphenyl)-N-methylserine was reported by F. G. Mann and C. E. Dalgliesh in the "Journal of Chemical Society" page 658 (1947) and also in the "Nature" 158, 375 (1946). They reported that this 3-(3,4-dihydroxyphenyl)-N-methylserine was obtained in a poor yield of only 3.5% by starting from 3,4-diethoxycarbonyloxybenzaldehyde and sarcosine methyl ester, and by interacting these compounds with each other and hydrolyzing the resultant 3-(3,4-diethoxycarbonyloxyphenyl)-N-methylserine methyl ester, followed by the deprotection of the protected 3- and 4-hydroxyl groups. However, they did not refer at all to the stereo chemistry of the 3-(3,4-dihydroxyphenyl)-N-methylserine they synthetized. It is therefore not known that said compound so synthetized by F. G. Mann et al was actually either in the threo-form or in the erythro-form or in the form of a mixture of the threo- and erythro-forms.
In the course of our study about the synthesis of 3-(3,4-dihydroxyphenyl)-N-methylserine, we have found that a 3-(3,4-dihydroxyphenyl)serine derivative of the general formula (II): ##STR1## wherein R.sub.1 represents a phenolic hydroxy-protecting group, preferably an aralkyl group such as benzyl, which is obtainable by interaction of 1 molar proportion of glycine with 2 molar proportions of an O-protected 3,4-dihydroxybenzaldehyde of the formula ##STR2## wherein R.sub.1 is as defined above in a known manner, can be isolated into the separate threo- and erythro-isomers. Based on this discovery and by our success in the subsequent conversion of each of these separate isomers so isolated into the corresponding N-methyl derivative while maintaining its original configuration, we have now successfully synthetized DL-threo-3-(3,4-dihydroxyphenyl)-N-methylserine and DL-erythro-3-(3,4-dihydroxyphenyl)-N-methylserine, respectively.
DL-Threo-3-(3,4-dihydroxyphenyl)-N-methylserine thus synthetized by us has never been described in any literature, but is believed to be a new compound. It is note worthy that the melting point of the DL-threo-3-(3,4-dihydroxyphenyl)-N-methylserine so produced by us is 163.degree.-165.degree. C. (with decomposition) which is clearly different from the melting point (221.degree.223.degree. C. with decomposition) of the DL-erythro-3-(3,4-dihydroxyphenyl)-N-methylserine so produced by us and also is far different from the melting point (233.degree. C. with decomposition) given by C. E. Dalgliesh et al in the literature for their 3-(3,4-dihydroxyphenyl)-N-methylserine.
Furthermore, we have now succeeded in isolating L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine from the DL-form of threo-3-(3,4-dihycroyphenyl)-N-methylserine according to a particular optical resolution method we have now devised and described hereinafter.